The qualitative and quantitative acquisition of morphological, functional and biochemical parameters using imaging methods is the basis for a plurality of medical research and application areas. Two known imaging methods are magnetic resonance imaging (MRI) and optical imaging techniques.
Magnetic resonance imaging (MRI) or nuclear magnetic resonance (NMR)1 is an existing powerful non-invasive medical imaging technique for producing three-dimensional cross-sectional images to visualize the inside of living organisms. It is primarily used to demonstrate pathological or other physiological alterations of living tissues. In short, medical MRI relies on the relaxation properties of excited hydrogen nuclei in water. When the object to be imaged is placed in a strong (several Tesla) uniform magnetic field the spins of the atomic nuclei with non-zero spin quantum numbers align parallel or anti-parallel to the magnetic field. The imaged object is then briefly exposed to radio frequency (RF) pulses in a plane perpendicular to the magnetic field, causing the magnetization to leave its equilibrium state. The precessing magnetization creates an altering flux in a nearby coil, the magnitude and phase of which are the MRI signal. In order to selectively image different locations of the object (i.e. spatial encoding of the signal phase), orthogonal magnetic field gradients are applied, and this data represents the spatial frequencies of the imaged object. Tomographic images can be reconstructed from the acquired data using e.g. the discrete Fourier transform. 1NMR generally is referred to the investigation of natural occurring frequency differences within a sample of probe chemical environment whereas MRI refers to the application of externally controlled frequency differences within a sample to probe water (proton) distribution.
In clinical practice, MRI is used to distinguish between tissues (e.g. pathologic tissue such as a tumor from normal tissue) exploiting the different magnetic properties of tissue: decay times (transverse relaxation time, T2, caused by the intrinsic spin-spin interaction; longitudinal relaxation, T1, the spin-lattice relaxation time), and proton density. From these, physiological tissue parameters such as diffusion, perfusion, etc. can be derived.
Further imaging methods for in-vivo examination of biological processes known in the state-of-the-art are optical imaging techniques including fluorescence and bioluminescence imaging. Fluorescence is the result of a process that occurs in certain molecules called fluorophores or fluorescent dyes. A fluorescent probe is a fluorophore designed to localize within a specific region of a biological specimen or to respond to a specific stimulus. In order to perform fluorescence imaging, a photon of certain energy is supplied by an external source such as an incandescent lamp or a laser and absorbed by the fluorophore, creating an excited electronic singlet state. This process distinguishes fluorescence from bioluminescence. It follows that another photon of lower energy is emitted, returning the fluorophore to its ground state. Using an appropriate sensor device, the emitted photons can be detected. Bioluminescence refers to the visible light emission in living organisms that accompanies the oxidation of organic compounds (luciferins) mediated by an enzyme catalyst (luciferase). Unlike fluorescence approaches, the imaged object does not need to be exposed to the light of an external light source. Bioluminescence imaging is carried out by tagging cells with a luciferase gene. These genetically engineered, light emitting cells can be followed throughout the imaged object by means of an appropriate sensor device. At present, fluorescence appears to be more generalizable, compared with bioluminescence imaging. Bioluminescence is more limited to genes and proteins. Its advantage is the use of an inserted reporter gene that can be tailored to specific processes.
Optical imaging has evolved into a potentially valuable tool for assessing functional properties. Examples include protein-protein interactions with cells, gene regulation at the transcription level, protein degradation over time, enzymatic activity associated with tumor progression, and cell death. Examples of ongoing applications include cancer, inflammatory disease, neurodegenerative disease, gastrointestinal physiology, renal physiology, cell trafficking, stem cell research, transplant science, and muscle physiology.
Optical planar imaging and optical tomography (OT) are emerging as alternative molecular imaging modalities, that detect light propagated through tissue at single or multiple projections. In the near future, optical tomography techniques are expected to improve considerably in spatial resolution by employing higher-density measurements and advanced photon technologies, e.g. based upon modulated intensity light or very short photon pulses. Clinical optical imaging applications will require high efficient photon collection systems. Primary interest for using an optical imaging technique lies in the non-invasive and non-hazardous nature of optical photons used, its low cost, its straightforward technology and most significantly in the availability of activatable probes that produce a signal only when they interact with their targets—as compared to radiolabelled probes used in PET (positron emission tomography) and SPECT (single photon emission computed tomography), which produce a signal continuously, independent of interacting with their targets, through the decay of the radioisotope. In OT, images are influenced greatly by the spatially dependent absorption and scattering properties of tissue. Boundery measurements from one or several sources and detectors are used to recover the unknown parameters from a transport model described, for instance, by a partial differential equation. The contrast between the properties of diseased and healthy tissue can be used in clinical diagnosis.
In the state of the art optical imaging detectors are known either to employ photo detector devices, e.g. CCD cameras, which are placed at a certain distance from, but not in contact with the imaged object, or to employ fibre-optics which bring the detector in contact with the imaged object.
The majority of existing optical imaging approaches are using CCD cameras. CCDs (charge coupled devices) are charge coupled imaging sensors that serve for highly sensitive detection of photons. The CCD camera is divided into a multiplicity of small light-sensitive zones (pixels) which produce the individual pixels of a two-dimensional image. The number of electrons is measured in each pixel, with the result that an image can be reconstructed. CCDs should be cooled since otherwise more electrons would be read out which would not be liberated as a result of the light incidence but rather as a result of heating. In order to define an optical field-of view, the CCD detector is typically coupled to a lens.
Almost all of the commercially available CCD based imaging designs generate only planar images of the integrated light distribution emitted from the surface of the imaged object, e.g. an animal. Market leader in the small animal optical imaging instrumentation arena is Xenogen Corp. Alameda, USA. The principle design of known CCD based optical imaging systems as used for in vivo fluorescence and bioluminescence imaging comprises a CCD camera, which is arranged at a certain distance to the imaged object (non-contact measurement) and aimed at this object in order to detect photons emitted from the object. Since CCD detectors need to be equipped with a lens which does impose a minimal focal length CCD cameras tend to be rather bulky instruments yielding large imaging compartments. If eventually used for tomographic imaging, a CCD-based camera system needs to be rotated around the imaged object in order to collect projection views or a multitude of cameras needs to be used in parallel. In another potential application lens-based CCD camera systems of the prior art cannot be positioned within the field-of-view of another imaging modality with the purpose of dual-modality image acquisition such as positron emission tomography (PET) for simultaneous PET/optical imaging.
Known fibre optics based optical imaging designs are being used in a way that the fibre ending tips are placed in contact with the object to be imaged. One of the reasons is that a particular fibre ending tip does not have a distinct well-defined field-of-view which would allow for backtracking a photon's incoming direction. In order to be resolvable for imaging, the imaged object, such as a mouse, needs to be put into a preferably cylindrical compartment which is filled with an appropriate liquid having specific optical properties. This is considered a significant drawback because of animal handling issues, experimental complexity and study management.
In the two pending international applications PCT/EP2006/061474 and PCT/EP2006/061475, a novel micro-lens array based optical imaging detector and a dual-modality imaging concept with a combination of positron emission tomography (PET) and optical imaging are described.
In the state of the art MR imaging and optical imaging are two imaging techniques, which are usually applied separately, using two separate devices successively. Although optical tomography provides functional and molecular information with a very high sensitivity, a major problem in optical imaging is its low spatial resolution and, hence, a lack of anatomical information. This problem which is also known for PET and single photon emission computer tomography (SPECT) imaging is amplified in optical tomography even more, when activatable probes are used that create no background. The generated signal has, if at all, only a weak correlation with surrounding morphological structure, especially in applications with novel, very specific tracers or cell trafficking studies. Thus, PET and SPECT scanners are nowadays often combined with CT, PET, and recently with MRI, to provide anatomical and functional information at the same time. While (at the current state of the art) CT provides excellent contrast for bone structures, magnetic resonance imaging (MRI) yields excellent soft tissue contrast. Therefore and for its illustrated highly complementary use in medicine/research, it would be desirable to combine the diagnostic benefits of an optical imaging scanner with those of an MRI scanner. While morphological imaging procedures such as magnetic resonance imaging in general have difficulties differentiating viable tumor from tumor necrosis or scar tissue, functional/molecular data such as those provided by optical imaging typically support only limited anatomical information which makes it difficult to render the accurate localization of the lesion.
The co-registration of sequentially acquired optical and MR images is described e.g. in Masciotti, J; Abdoulaev, G et al., “Combined optical tomographic and magnetic resonance imaging of tumor bearing mice”, Proc. SPIE, Vol. 5693, pp. 74-81, 2005; Springett H. Dehghani B W, et al. “Coregistration Of Dynamic Contrast Enhanced MRI and Broadband Diffuse Optical Spectroscopy for Characterizing Breast Cancer”, Technology in Cancer Research & Treatment, vol. 4, pp. 549-558, 2005; Siegel A M, Culver JP et al. “Temporal comparison of functional brain imaging with diffuse optical tomography and FMRI during rat forepaw stimulation”, Phys. Med. Biol., vol. 48, pp. 1391-1403, 2003, which illustrates the desire to achieve combined optical and MR images.
A comparison of the images obtained by the two sequentially applied imaging methods is possible only to a limited extent since they cannot be obtained simultaneously. The problems of excessive and prolonged burdening of the subject to be examined, the non-reproducibility of kinetic studies, the non-identical imaging geometries, animal and organ movement and the correct superposition of the images arise, when the two methods are carried out successively.
EP 1 559 363 A2 refers to an apparatus for providing optical and anatomical diagnostic imaging. The apparatus comprises an anatomical imaging unit for inserting into a body cavity, wherein the anatomical imaging unit acquires anatomical images of the body cavity and an optical imaging unit substantially enclosed within a substantially translucent portion of the anatomical imaging unit, wherein the optical imaging unit detects fluorescence in the body cavity. According to one embodiment, the anatomical imaging unit comprises a magnetic resonance imaging component for acquiring magnetic resonance images of the body cavity.
Paul D. Majors et al.: “A combined confocal and magnetic resonance microscope for biological studies”, Review of Scientific Instruments, vol. 73, no. 12, pages 4329-4338 describes a novel microscope for studying live cells simultaneously with both confocal scanning laser fluorescence optical microscopy and magnetic resonance microscopy.
Combined optical/MR imaging systems, where the optical detector is in contact with the imaged object, have been described recently [Xu H, Springett, R et al., “Magnetic-resonance-imaging-coupled broadband near-infrared tomography system for small animal brain studies”, Applied Optics, vol. 44, pp. 2177-2188, 2005; Ntziachristos V, Yodh AG, et al., “MRI-Guided Diffuse Optical Spectroscopy of Malignant and Benign Breast Lesions” Neoplasia, vol. 4, pp. 347-354, 2002]. While such setup is well suited for basic experimental (phantom) studies, contact imaging has significant limitations since fiber-based detection leads to insufficient spatial sampling and field-of-view, and further constraints on the reconstruction algorithm. Moreover, positioning and contact issues which mostly are coped with by using matching fluids complicate experimental procedures and contribute to unnecessary photon diffusion and light attenuation.